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    An hACE2 peptide mimic blocks SARS-CoV-2 Pulmonary Cell Infection MESHD

    Authors: Philippe Karoyan; Vincent Vieillard; Estelle Odile; Alexis Denis; Luis Gomes-Morales; Pascal Grondin; Olivier Lequin; Ruan Jishou; Duan Guangyou; Li Xin; Drew M Titmarsh; Mark J Smyth; Christian R Engwerda; Kelli PA MacDonald; Tobias Bald; David E James; James Edward Hudson; Rong Zhang; Arthur G Calise; Bradley L Pulver; Dominic Ruocco; Greggory E Mojares; Michael P Eagan; Kristy L Ziontz; Paul Mastrokyriakos; Stuart L Goldberg; Felecia Cerrato; Maha Farhat; Damien Slater; Jason B Harris; John Branda; David Hooper; Jessie M Gaeta; Travis P. Baggett; James O'Connell; Andreas Gnirke; Tami D Lieberman; Anthony Philippakis; Meagan Burns; Catherine Brown; Jeremy Luban; Edward T Ryan; Sarah E Turbett; Regina C LaRocque; William P. Hanage; Glen Gallagher; Lawrence C Madoff; Sandra Smole; Virginia M. Pierce; Eric S Rosenberg; Pardis Sabeti; Daniel J Park; Bronwyn L MacInnis

    doi:10.1101/2020.08.24.264077 Date: 2020-08-24 Source: bioRxiv

    In the light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site and have a high helical folding propensity in aqueous solution. Our best peptide mimic binds to the virus spike protein with high affinity and is able to block SARS-CoV-2 human pulmonary cell infection MESHD with an inhibitory concentration (IC50) in the nanomolar range. This first in class blocking peptide mimic represents a powerful tool that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease MESHD 2019 (COVID-19). In BriefHelical peptide mimicking H1 helix of hACE2 and composed of only natural amino acids binds to SARS-CoV-2 spike protein with high affinity and blocks human pulmonary cells infection with IC50 in the nM range. HighlightsA peptide mimic of hACE2 designed from H1 helix and composed of only natural amino acids show high helical folding propensity in aqueous media. This peptide mimic binds to virus spike RBD with high affinity (sub-nM range). This peptide mimic blocks SARS-CoV-2 pulmonary cells infection with an IC50 in the nM range. This peptide mimic is devoid of toxicity on pulmonary cells.

    Safety and Feasibility of Umbilical Cord Mesenchymal Stem Cells in Patients with COVID-19 Pneumonia HP: A Pilot Study

    Authors: Ying Feng; Jianying Huang; Jianyuan Wu; Yan Xu; Bo Chen; Lijun Jiang; Hui Xiang; Zhiyong Peng; Xinghuan Wang

    doi:10.21203/rs.3.rs-62218/v1 Date: 2020-08-19 Source: ResearchSquare

    Background: We aim to explore the safety and feasibility of umbilical cord mesenchymal stem cells (UC-MSCs) transplantation in severe and critically severe type Coronavirus disease MESHD 2019 (COVID-19) patients.Methods: In addition to normal therapy, we performed four times transplantation of UC-MSCs MESHD in 16 severe and critically severe type COVID-19 patients. We observed adverse events from enrollment to D28. We evaluated the oxygenation index, inflammatory biomarkers, chest imaging, lymphocyte subsets count et al on the 7th day (D7±1 day), the 14th day (D14±1 day) and the 28th day (D28±3 days).Results: There were no infusion-related or allergic reactions MESHD. The oxygenation index was improved after transplantation. The mortality of enrolled patients was 6.25%. The level of cytokines estimated was varied in normal range, the chest imaging was improved, the lymphocyte count and lymphocyte subsets count were recovered after transplantation.Conclusions: Intravenous transplantation of UC-MSCs was safe and feasible for treatment in patients with COVID-19 pneumonia HP pneumonia MESHD.Trial registration: Clinical Trial, NCT04269525. Registered 7 February 2020. https://clinicaltrials.gov/ct2/show/NCT04269525

    SARS-CoV-2 manipulates the SR-B1-mediated HDL uptake pathway for its entry

    Authors: Congwen Wei; Luming Wan; Qiulin Yan; Xiaolin Wang; Jun Zhang; Yanhong Zhang; Jin Sun; Xiaopan Yang; Jing Gong; Chen Fan; Xiaoli Yang; Yufei Wang; Xuejun Wang; Jianmin Li; Huan Yang; Huilong Li; Zhe Zhang; Rong Wang; Peng Du; Yulong Zong; Feng Yin; Wanchuan Zhang; Yumeng Peng; Haotian Lin; Rui Zhang; Wei Chen; Qi Gao; Yuan Cao; Hui Zhong

    doi:10.1101/2020.08.13.248872 Date: 2020-08-14 Source: bioRxiv

    The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection MESHD. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody SERO)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection MESHD. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry MESHD and could provide a new target to treat SARS-CoV-2 infection MESHD.

    Focus on renal blood SERO flow in mechanically ventilated patients with SARS-CoV-2

    Authors: Alberto Fogagnolo; Salvatore Grasso; Martin Dres; Loreto Gesualdo; Elena Morelli; Irene Ottaviani; Elisabetta Marangoni; Carlo Alberto Volta; Savino Spadaro

    doi:10.21203/rs.3.rs-57589/v1 Date: 2020-08-11 Source: ResearchSquare

    Background: Patients with ARDS MESHD due to the severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2) seem particularly susceptible to AKI. Our hypothesis was that the renal blood SERO flow could be more compromised in SARS-CoV-2 patients than in patients with “traditional” ARDS. We compared the renal resistivity index (RRI) and the renal venous flow ( RVF MESHD) in ARDS MESHD patients with SARS-CoV-2 and in ARDS MESHD patients due to other etiologies.Materials and Methods: Prospective, observational study performed on 30 mechanically ventilated patients (15 with SARS-COV-2 ARDS and 15 with ARDS). Ultrasound Doppler measurements of RRI and RVF MESHD pattern were performed in each patient.Results: Patients with SARS-COV-2 ARDS had higher RRI than patients with ARDS (0.71[0.67–0.78] vs 0.64[0.60–0.74], p=0.04). RVF was not-continuous in 9/15 patients (71%) in the SARS-COV-2 ARDS group and in and 5/15 (33%) in the ARDS group (p=0.27). A linear correlation was found between PEEP and RRI MESHD in patients with SARS-COV-2 ARDS (r2=0.31; p=0.03) but not in patients with ARDS. Occurrence of AKI was 53% in patients with SARS-COV-2 ARDS and 33% in patients with ARDS (p=0.46).Conclusions: We found a more pronounced impairment in renal blood MESHD blood SERO flow in mechanically ventilated patients with SARS-COV-2 ARDS, compared with patients with “traditional” ARDS. 

    Lymphopenia HP Lymphopenia MESHD-induced T cell proliferation is a hallmark of severe COVID-19

    Authors: Sarah Adamo; Stéphane Chevrier; Carlo Cervia; Yves Zurbuchen; Miro E. Räber; Liliane Yang; Sujana Sivapatham; Andrea Jacobs; Esther Bächli; Alain Rudiger; Melina Stüssi-Helbling; Lars C. Huber; Dominik Schaer; Bernd Bodenmiller; Onur Boyman; Jakob Nilsson

    doi:10.1101/2020.08.04.236521 Date: 2020-08-04 Source: bioRxiv

    Coronavirus disease MESHD 2019 (COVID-19), caused by infection with severe HP infection with severe MESHD acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), has a broad clinical presentation ranging from asymptomatic TRANS infection to fatal disease. Different features associated with the immune response to SARS-CoV-2, such as hyperinflammation and reduction of peripheral CD8+ T cell counts are strongly associated with severe disease. Here, we confirm the reduction in peripheral CD8+ T cells both in relative and absolute terms and identify T cell apoptosis and migration into inflamed tissues as possible mechanisms driving peripheral T cell lymphopenia MESHD lymphopenia HP. Furthermore, we find evidence of elevated serum SERO interleukin-7, thus indicating systemic T cell paucity MESHD and signs of increased T cell proliferation in patients with severe lymphopenia HP lymphopenia MESHD. Following T cell lymphopenia HP lymphopenia MESHD in our pseudo-longitudinal time course, we observed expansion and recovery of poly-specific antiviral T cells, thus arguing for lymphopenia HP lymphopenia MESHD-induced T cell proliferation. In summary, this study suggests that extensive T cell loss and subsequent T cell proliferation are characteristic of severe COVID-19.

    Prognostic Significance of COVID-19 Receptor ACE2 and Recommendation For Anti- Hypertensive Drug in Renal Cell Carcinoma MESHD Renal Cell Carcinoma HP

    Authors: Kihun Kim; Yeji Ko; Dai Sik Ko; Yun Hak Kim

    doi:10.21203/rs.3.rs-49602/v1 Date: 2020-07-27 Source: ResearchSquare

    Background: Owing to its worldwide spread, the coronavirus disease MESHD (COVID-19) epidemic was declared a pandemic by the World Health Organization on March 11, 2020. Angiotensin-converting enzyme 2 (ACE2) is the outer surface protein of the cell membrane that is abundantly distributed in the heart, lungs, and kidneys, and plays an important role in molecular docking of the severe acute respiratory syndrome coronavirus 2 MESHD. In this study, we aimed to analyze the difference in the survival rate according to ACE2 expressions in pan- cancer MESHD. Methods: The clinical and genomic data of pan- cancer MESHD patients were accessed from The cancer MESHD Genome Atlas. To identify the prognostic significance of ACE2, we used Kaplan-Meier with log-rank test, and the Cox proportional hazards regression to analyze prognostic significance. Results: In the Kaplan-Meier curve, clear cell renal cell carcinoma HP clear cell renal cell carcinoma MESHD ( ccRCC MESHD), uveal melanoma HP melanoma MESHD, and prostate adenocarcinoma MESHD showed statistically significant. In the Cox regression, thyroid carcinoma HP thyroid carcinoma MESHD and glioblastoma multiforme HP glioblastoma multiforme MESHD, and ccRCC MESHD showed significant results. Only ccRCC MESHD had statistically significant, and high ACE2 expression is related to good prognosis. Conclusions: It is known that ACE inhibitor, a primary antihypertensive agent, increases ACE2 expression. Based on these results, we believe that the ACE inhibitor will be important to increase the lifespan of ccRCC MESHD patients. This study is the first research to offer a recommendation on the use of anti- hypertensive MESHD drugs to ccRCC MESHD patients.

    Renal carcinoma MESHD carcinoma HP is associated with increased risk of coronavirus infections MESHD

    Authors: Satyendra C Tripathi; Vishwajit Deshmukh; Chad J. Creighton; Ashlesh Patil

    doi:10.1101/2020.07.02.184663 Date: 2020-07-06 Source: bioRxiv

    The current pandemic COVID-19 has affected most severely to the people with old age TRANS, or with comorbidities such as hypertension HP hypertension MESHD, diabetes mellitus HP diabetes mellitus MESHD, chronic kidney disease HP chronic kidney disease MESHD, COPD MESHD, and cancers MESHD. Cancer MESHD patients are twice more likely to contract the disease because of the malignancy MESHD or treatment-related immunosuppression; hence identification of the vulnerable population among these patients is essential. It is speculated that along with ACE2, other auxiliary proteins MESHD (DPP4, ANPEP, ENPEP, TMPRSS2) might facilitate the entry of coronaviruses in the host cells. We took a bioinformatics approach to analyze the gene and protein expression data of these coronavirus receptors in human normal and cancer MESHD tissues of multiple organs. Here, we demonstrated an extensive RNA and protein expression profiling analysis of these receptors across solid tumors MESHD and normal tissues. We found that among all, renal tumor MESHD and normal tissues exhibited increased levels of ACE2, DPP4, ANPEP, and ENPEP. Our results revealed that TMPRSS2 may not be the co-receptor for coronavirus in renal carcinoma MESHD carcinoma HP patients. The receptors’ expression levels were variable in different tumor MESHD stage, molecular and immune subtypes of renal carcinoma MESHD carcinoma HP. In clear cell renal cell carcinomas HP clear cell renal cell carcinomas MESHD, coronavirus receptors were associated with high immune infiltration, markers of immunosuppression, and T cell exhaustion. Our study indicates that CoV receptors may play an important role in modulating the immune infiltrate and hence cellular immunity in renal carcinoma MESHD carcinoma HP. As our current knowledge of pathogenic mechanisms will improve, it may help us in designing focused therapeutic approaches.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Menstrual blood SERO-derived mesenchymal stem cells provide new insights into the treatment of coronavirus disease MESHD 2019 (COVID-19)

    Authors: Xin Chen; Liang Yu; Lijun Chen; Xiaoqin Zheng; Lingling Tang; Kaijin Xu; Hongliu Cai; Yu Chen; Shufa Zheng; Juan Lu; Zhenyu Xu; Qiang Zhang; Hainv Gao; Yifei Li; Jingjing Qu; Yingan Jiang; Xiaowei Xu; Charlie Xiang; Lanjuan Li

    doi:10.21203/rs.3.rs-25947/v1 Date: 2020-04-29 Source: ResearchSquare

    Background: The coronavirus disease MESHD 2019 (COVID-19) causing a cluster of respiratory infections MESHD in Wuhan, China, is identified in December 2019. The main symptoms are defined as fever HP fever MESHD, cough HP cough MESHD, shortness of breath MESHD, with early symptom of sputum, acute respiratory distress syndrome MESHD respiratory distress HP syndrome ( ARDS MESHD), and the final lung injury MESHD and pulmonary fibrosis HP pulmonary fibrosis MESHD. Currently, there is no effective method to cure it. Mesenchymal stem cell (MSC) therapy is an immediate need for treating COVID-19 especially severe patients at present.Methods: We describe the two confirmed case TRANS of COVID-19 severe patients in Hangzhou, China to explore the role of menstrual blood SERO-derived MSC in the treatment of SARS-CoV-2 infection MESHD. Furthermore, we mimic disease model of pulmonary fibrosis HP pulmonary fibrosis MESHD in mice to assess the role of MSC. Then, a co-culture system to investigate the underlying mechanism between MSC and pulmonary-associated cells by a series of Physiological, biochemical, bioinformatics analysis.Results: MSC transplantation increases the immune indicators (including lymphocytes) and decreases inflammatory indicators (such as IL-6, IL-10, TNF, and IFN). More importantly, the two patients alleviated symptom and discharged after 3 weeks’ treatment with MSC MESHD. Additionally, MSCs exhibit an anti-inflammatory role through suppressing some inflammatory factors (RANTES, GM-CSF, MIG-1g, MCP-5, Eotaxin), which is anastomotic to current clinical study using MSC to treat COVID-19. Conclusions: This is the first report using menstrual blood SERO-derived MSC in treating COVID-19 patients. From our clinical results, we hold one idea that MSCs reduced inflammatory effect to defend cytokine storm. The underlying mechanism is probably that MSCs inhibit epithelia cell apoptosis and reduce the secretion of inflammatory factors to prevent myofibroblasts activity. MSC provides an alternative method for treating COVID-19 particularly some patients with ARDS MESHD or subsequent pulmonary fibrosis HP pulmonary fibrosis MESHD.Trial registration: This clinical trial was submitted to and approved by the Ethics Committee of the First Affiliated Hospital, Collage of Medicine, Zhejiang University. MSC administration in patient with COVID-19 was conducted in a single center and open-label clinical trial (ChiCTR2000029606).

    Medical Countermeasures Analysis of 2019-nCoV and Vaccine Risks for Antibody SERO-Dependent Enhancement (ADE)

    Authors: Darrell O. Ricke; Robert W. Malone

    id:10.20944/preprints202003.0138.v1 Date: 2020-03-08 Source: Preprints.org

    Background: In 80% of patients, COVID-19 presents as mild disease1,2. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome MESHD, but include a T-predominant lymphopenia3, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation HP including immunosuppression4. Methods: All major SARS-CoV-2 proteins MESHD were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non- neutralizing antibodies SERO to variable S domains may enable an alternative infection MESHD pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV5,6 SARS-CoV-17-10 and Middle East Respiratory Syndrome coronavirus (MERS-CoV MESHD) 11 demonstrate vaccination-induced antibody SERO-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection MESHD; pan-T depletion is present in severe COVID-19 disease3 and may be accelerated by APC infection MESHD. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection MESHD and T-cell depletion12 13. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.

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